Pub Date : 2025-08-21DOI: 10.1016/j.mvr.2025.104861
Mohamed J. Saadh , Omer Qutaiba B. Allela , Radhwan Abdul Kareem , Lalji Baldaniya , R. Roopashree , Vishal Thakur , Manpreet Kaur , Abdusamat Valiev , Hayder Naji Sameer , Ahmed Yaseen , Zainab H. Athab , Mohaned Adil
Angiogenesis is critical for effective wound healing, supplying oxygen and nutrients to regenerating tissues. In chronic conditions like diabetes, impaired angiogenesis leads to delayed healing, chronic wounds, and significant healthcare burdens. Exosomes, nano-sized extracellular vesicles derived from cells such as mesenchymal stem cells (MSCs), amniotic epithelial cells, and keratinocytes, have emerged as key mediators in promoting angiogenesis. Laden with bioactive cargos—including microRNAs, proteins, and lipids—exosomes orchestrate endothelial cell proliferation, migration, and extracellular matrix remodeling to enhance vascularization. This review explores the molecular mechanisms by which exosomes drive angiogenesis, highlighting their role in modulating signaling pathways and immune responses critical for tissue repair. We evaluate the therapeutic promise of exosome-based delivery systems, integrating insights from biological, pharmaceutical, and cell-based approaches. By leveraging these advancements, exosomal therapies offer transformative potential for managing chronic wounds and ischemic conditions, paving the way for innovative regenerative medicine strategies.
{"title":"Harnessing exosomal mediators for advanced wound healing: Mechanisms and therapeutic potential in angiogenesis","authors":"Mohamed J. Saadh , Omer Qutaiba B. Allela , Radhwan Abdul Kareem , Lalji Baldaniya , R. Roopashree , Vishal Thakur , Manpreet Kaur , Abdusamat Valiev , Hayder Naji Sameer , Ahmed Yaseen , Zainab H. Athab , Mohaned Adil","doi":"10.1016/j.mvr.2025.104861","DOIUrl":"10.1016/j.mvr.2025.104861","url":null,"abstract":"<div><div>Angiogenesis is critical for effective wound healing, supplying oxygen and nutrients to regenerating tissues. In chronic conditions like diabetes, impaired angiogenesis leads to delayed healing, chronic wounds, and significant healthcare burdens. Exosomes, nano-sized extracellular vesicles derived from cells such as mesenchymal stem cells (MSCs), amniotic epithelial cells, and keratinocytes, have emerged as key mediators in promoting angiogenesis. Laden with bioactive cargos—including microRNAs, proteins, and lipids—exosomes orchestrate endothelial cell proliferation, migration, and extracellular matrix remodeling to enhance vascularization. This review explores the molecular mechanisms by which exosomes drive angiogenesis, highlighting their role in modulating signaling pathways and immune responses critical for tissue repair. We evaluate the therapeutic promise of exosome-based delivery systems, integrating insights from biological, pharmaceutical, and cell-based approaches. By leveraging these advancements, exosomal therapies offer transformative potential for managing chronic wounds and ischemic conditions, paving the way for innovative regenerative medicine strategies.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104861"},"PeriodicalIF":2.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To investigate the hypothesis that the wall-to-lumen ratio (WLR) of retinal arteries is predictive of morbidity and mortality in patients with end-stage chronic kidney disease (CKD).
Methods
Prospective single center clinical study. In 83 patients with CKD (average age (±SD) 75.8 (±11.4) years), arterial metrics in the retinal vasculature were measured using adaptive optics ophthalmoscopy (AOO; rtx1, ImagineEyes, France). Multivariate analysis including vascular metrics and biological parameters was done to identify predictive risk factors of the morbidity and mortality rates at 3 years.
Results
At inclusion, the mean (±SD) wall-to-lumen ratio (WLR) was 0,34 (± 0,17). No correlation was found between blood pressure and the WLR. The 1, 2 and 3-year survival rates were 74.7 %, 57.3 % and 42.1 %, respectively. The 1, 2 and 3-year rates of nonfatal cardiovascular events were 25.3 %, 42.7 % and 56.5 %, respectively. Four patients were lost to follow-up. Based on a Cox model, the cumulative 3-year relative risk of death or cardiovascular event was inversely correlated to the initial WLR (RR 2.5 if WLR <0.36, 2.1 if <0.3, 4.9 if <0.27), age over 80 years (RR 1.9), and sedentarity (RR 2.3). Metabolic factors were not predictive of event-free survival.
Conclusions
In patients with end-stage CKD, a lower WLR is associated with a higher morbidity and mortality rate at 3 years. Retinal vascular metrics may therefore provide novel biomarkers for the prediction of event-free survival in CKD. Additional studies are necessary to elucidate the underlying relationship.
{"title":"Prognostic value of the wall-to-lumen ratio of retinal arteries in patients with end-stage chronic kidney disease","authors":"Céline Faure , Cindy Castrale , Anaïs Benabed , Romain Lezé , Pauline Cognard , Michel Paques","doi":"10.1016/j.mvr.2025.104860","DOIUrl":"10.1016/j.mvr.2025.104860","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the hypothesis that the wall-to-lumen ratio (WLR) of retinal arteries is predictive of morbidity and mortality in patients with end-stage chronic kidney disease (CKD).</div></div><div><h3>Methods</h3><div>Prospective single center clinical study. In 83 patients with CKD (average age (±SD) 75.8 (±11.4) years), arterial metrics in the retinal vasculature were measured using adaptive optics ophthalmoscopy (AOO; rtx1, ImagineEyes, France). Multivariate analysis including vascular metrics and biological parameters was done to identify predictive risk factors of the morbidity and mortality rates at 3 years.</div></div><div><h3>Results</h3><div>At inclusion, the mean (±SD) wall-to-lumen ratio (WLR) was 0,34 (± 0,17). No correlation was found between blood pressure and the WLR. The 1, 2 and 3-year survival rates were 74.7 %, 57.3 % and 42.1 %, respectively. The 1, 2 and 3-year rates of nonfatal cardiovascular events were 25.3 %, 42.7 % and 56.5 %, respectively. Four patients were lost to follow-up. Based on a Cox model, the cumulative 3-year relative risk of death or cardiovascular event was inversely correlated to the initial WLR (RR 2.5 if WLR <0.36, 2.1 if <0.3, 4.9 if <0.27), age over 80 years (RR 1.9), and sedentarity (RR 2.3). Metabolic factors were not predictive of event-free survival.</div></div><div><h3>Conclusions</h3><div>In patients with end-stage CKD, a lower WLR is associated with a higher morbidity and mortality rate at 3 years. Retinal vascular metrics may therefore provide novel biomarkers for the prediction of event-free survival in CKD. Additional studies are necessary to elucidate the underlying relationship.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104860"},"PeriodicalIF":2.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-20DOI: 10.1016/j.mvr.2025.104859
Maya Salame, Marianne Fenech
The formation of the cell-free layer (CFL) near vessel walls plays a critical role in microcirculatory function, influencing blood rheology, oxygen delivery, and endothelial interactions. While hematocrit (Ht) is a well-established determinant of CFL thickness, the influence of shear-related parameters remains debated due to conflicting findings in the literature. In this study, we systematically quantified the optical CFL thickness () in circular glass microchannels (25–50 μm diameter) under varying hematocrit levels (5–20 %), flow rates, and suspension media (phosphate-buffered saline and plasma). High-resolution microfluidic imaging and micro-particle image velocimetry (μPIV) were used to extract local velocity fields and calculate shear rate gradients (∇).
Rather than treating ∇ as an imposed variable, we characterize it as a flow-derived descriptor of the local hydrodynamic environment. Across conditions, ∇ showed stronger correlations with CFL thickness than bulk shear rate. In PBS, increasing ∇ was associated with reduced CFL thickness, likely due to enhanced shear-induced dispersion. In contrast, in plasma, higher ∇ values promoted disaggregation of red blood cell (RBC) aggregates and restored hydrodynamic lift, resulting in thicker CFLs. These trends underscore the importance of considering both the suspension medium and spatial shear variations when interpreting RBC behavior.
Comparison with prior in vitro, in vivo, and computational studies suggests that discrepancies in reported CFL trends can often be reconciled by accounting for differences in aggregation potential and local shear rate gradients. This work provides a unified experimental framework for interpreting CFL dynamics and highlights ∇ as a valuable parameter for describing flow-mediated RBC redistribution in the microcirculation.
{"title":"Key contributors to cell-free layer formation: An experimental investigation of hematocrit and shear rate gradient","authors":"Maya Salame, Marianne Fenech","doi":"10.1016/j.mvr.2025.104859","DOIUrl":"10.1016/j.mvr.2025.104859","url":null,"abstract":"<div><div>The formation of the cell-free layer (CFL) near vessel walls plays a critical role in microcirculatory function, influencing blood rheology, oxygen delivery, and endothelial interactions. While hematocrit (Ht) is a well-established determinant of CFL thickness, the influence of shear-related parameters remains debated due to conflicting findings in the literature. In this study, we systematically quantified the optical CFL thickness (<span><math><msub><mi>δ</mi><mi>o</mi></msub></math></span>) in circular glass microchannels (25–50 μm diameter) under varying hematocrit levels (5–20 %), flow rates, and suspension media (phosphate-buffered saline and plasma). High-resolution microfluidic imaging and micro-particle image velocimetry (μPIV) were used to extract local velocity fields and calculate shear rate gradients (∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span>).</div><div>Rather than treating ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> as an imposed variable, we characterize it as a flow-derived descriptor of the local hydrodynamic environment. Across conditions, ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> showed stronger correlations with CFL thickness than bulk shear rate. In PBS, increasing ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> was associated with reduced CFL thickness, likely due to enhanced shear-induced dispersion. In contrast, in plasma, higher ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> values promoted disaggregation of red blood cell (RBC) aggregates and restored hydrodynamic lift, resulting in thicker CFLs. These trends underscore the importance of considering both the suspension medium and spatial shear variations when interpreting RBC behavior.</div><div>Comparison with prior in vitro, in vivo, and computational studies suggests that discrepancies in reported CFL trends can often be reconciled by accounting for differences in aggregation potential and local shear rate gradients. This work provides a unified experimental framework for interpreting CFL dynamics and highlights ∇<span><math><mover><mi>γ</mi><mo>̇</mo></mover></math></span> as a valuable parameter for describing flow-mediated RBC redistribution in the microcirculation.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104859"},"PeriodicalIF":2.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-20DOI: 10.1016/j.mvr.2025.104862
Stanislav Dil, Vyacheslav Ryabov, Leonid Maslov, Olga Mochula, Andrey Mochula, Maria Kercheva, Konstantin Zavadovsky, Evgeny Vyshlov
Background
Refractory no-reflow correlates with worse outcomes, including larger infarct sizes, impaired ventricular function, and higher mortality rates, despite advances in percutaneous coronary intervention (PCI). Microvascular obstruction (MVO) and increased left ventricular end-diastolic pressure (LVEDP) are implicated in the pathogenesis, potentially exacerbating ischemic injury and limiting myocardial recovery. While pressure-wire–derived indices such as the Index of Microcirculatory Resistance (IMR) have been validated against MRI-defined MVO in STEMI populations, their invasive nature and procedural complexity limit broad adoption. In contrast, combining dynamic SPECT and cardiac MRI enables a comprehensive non-invasive functional-structural evaluation of coronary microvascular function in refractory no-reflow.
Methods
This study is a post hoc analysis of a larger randomized controlled trial (RCT) evaluating the efficacy and safety of intracoronary epinephrine in patients with refractory no-reflow post-PCI (ClinicalTrials.govNCT04573751). We evaluated global coronary flow metrics (RMBF, SMBF, gRFI) derived from SPECT and assessed structural markers of microvascular injury (infarct size, MVO) on MRI. Echocardiographic estimations of LVEDP were also analyzed.
Results
Dynamic SPECT revealed suboptimal stress myocardial blood flow in most patients, highlighting microvascular impairment. Elevated estimated LVEDP was significantly correlated with indexed MVO (rs = 0.678, p = 0.001). Traditional flow reserve metrics showed limited sensitivity, whereas global relative flow increase (gRFI) showed a statistically significant correlation with MVO, highlighting its added value in detecting stress-induced perfusion abnormalities. Given the small sample and potential outlier influence, this observation should be considered hypothesis-generating.
Conclusion
Our findings support that functional impairments—particularly elevated LVEDP and reduced gRFI—are associated with refractory no-reflow. In particular, gRFI may serve as a promising non-invasive marker of microvascular dysfunction, complementing structural imaging. None-theless, further validation in larger cohorts is needed. This study advocates for refined multimodal imaging strategies and tailored therapeutic approaches targeting dynamic microvascular disturbances to improve outcomes in refractory no-reflow.
背景：尽管经皮冠状动脉介入治疗（PCI）技术有所进步，但难治性非再流与更糟糕的结果相关，包括更大的梗死面积、心室功能受损和更高的死亡率。微血管阻塞（MVO）和左室舒张末期压（LVEDP）升高与发病机制有关，可能加剧缺血性损伤并限制心肌恢复。虽然压力线衍生的指标，如微循环阻力指数（IMR）已经在STEMI人群中针对mri定义的MVO进行了验证，但其侵入性和程序复杂性限制了其广泛采用。相比之下，结合动态SPECT和心脏MRI可以对难治性无血流障碍患者的冠状动脉微血管功能进行全面的无创功能结构评估。方法：本研究是一项大型随机对照试验（RCT）的事后分析，该试验评估了冠状动脉内肾上腺素治疗难治性pci后无再流患者的有效性和安全性（ClinicalTrials.gov NCT04573751）。我们评估了SPECT得出的全球冠状动脉血流指标（RMBF， SMBF, gRFI），并评估了MRI上微血管损伤的结构标记（梗死面积，MVO）。超声心动图估计LVEDP也进行了分析。结果动态SPECT显示大多数患者的应激心肌血流量不理想，微血管损伤突出。估计LVEDP升高与MVO指数显著相关（rs = 0.678, p = 0.001）。传统的流量储备指标灵敏度有限，而全局相对流量增加（gRFI）与MVO的相关性具有统计学意义，突出了其在检测应力诱导的灌注异常方面的附加价值。考虑到样本小和潜在的异常值影响，这一观察结果应该被认为是假设生成。结论：我们的研究结果支持功能损伤——特别是LVEDP升高和grfi降低——与难治性无血流相关。特别是，gRFI可以作为微血管功能障碍的一种有前途的非侵入性标志物，补充结构成像。然而，需要在更大的队列中进一步验证。本研究提倡完善的多模式成像策略和针对动态微血管紊乱的量身定制的治疗方法，以改善难治性无再流的预后。
{"title":"Assessing coronary microvascular dysfunction in refractory no-reflow: Insights from dynamic myocardial perfusion scintigraphy and cardiac MRI","authors":"Stanislav Dil, Vyacheslav Ryabov, Leonid Maslov, Olga Mochula, Andrey Mochula, Maria Kercheva, Konstantin Zavadovsky, Evgeny Vyshlov","doi":"10.1016/j.mvr.2025.104862","DOIUrl":"10.1016/j.mvr.2025.104862","url":null,"abstract":"<div><h3>Background</h3><div>Refractory no-reflow correlates with worse outcomes, including larger infarct sizes, impaired ventricular function, and higher mortality rates, despite advances in percutaneous coronary intervention (PCI). Microvascular obstruction (MVO) and increased left ventricular end-diastolic pressure (LVEDP) are implicated in the pathogenesis, potentially exacerbating ischemic injury and limiting myocardial recovery. While pressure-wire–derived indices such as the Index of Microcirculatory Resistance (IMR) have been validated against MRI-defined MVO in STEMI populations, their invasive nature and procedural complexity limit broad adoption. In contrast, combining dynamic SPECT and cardiac MRI enables a comprehensive non-invasive functional-structural evaluation of coronary microvascular function in refractory no-reflow.</div></div><div><h3>Methods</h3><div>This study is a post hoc analysis of a larger randomized controlled trial (RCT) evaluating the efficacy and safety of intracoronary epinephrine in patients with refractory no-reflow post-PCI (<span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> <span><span>NCT04573751</span><svg><path></path></svg></span>). We evaluated global coronary flow metrics (RMBF, SMBF, gRFI) derived from SPECT and assessed structural markers of microvascular injury (infarct size, MVO) on MRI. Echocardiographic estimations of LVEDP were also analyzed.</div></div><div><h3>Results</h3><div>Dynamic SPECT revealed suboptimal stress myocardial blood flow in most patients, highlighting microvascular impairment. Elevated estimated LVEDP was significantly correlated with indexed MVO (rs = 0.678, <em>p</em> = 0.001). Traditional flow reserve metrics showed limited sensitivity, whereas global relative flow increase (gRFI) showed a statistically significant correlation with MVO, highlighting its added value in detecting stress-induced perfusion abnormalities. Given the small sample and potential outlier influence, this observation should be considered hypothesis-generating.</div></div><div><h3>Conclusion</h3><div>Our findings support that functional impairments—particularly elevated LVEDP and reduced gRFI—are associated with refractory no-reflow. In particular, gRFI may serve as a promising non-invasive marker of microvascular dysfunction, complementing structural imaging. None-theless, further validation in larger cohorts is needed. This study advocates for refined multimodal imaging strategies and tailored therapeutic approaches targeting dynamic microvascular disturbances to improve outcomes in refractory no-reflow.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104862"},"PeriodicalIF":2.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To measure retinal blood flow (RBF) in the retinal veins of patients with primary open-angle glaucoma (POAG) and to compare it with healthy controls. A secondary objective was to determine any correlation between RBF and visual field (VF) loss or retinal nerve-fiber layer (RNFL) thickness.
Method
Twelve patients with POAG and 11 healthy controls were included in a prospective single-center study. Our prototype Adaptive Optics Laser Doppler Velocimeter (AO-LDV) consisted of a laser Doppler velocimeter combined with an adaptive optic fundus camera (rtx1, Imagine Eyes®) allowing measurement of blood vessel diameter and therefore, calculation of blood flow within the vessel. Blood flow in the superior temporal vein (STV) was compared with that in the inferior temporal vein (ITV). All subjects underwent eye examinations including visual field (Humphrey 24-2 SITA-standard strategy) and measurement of retinal nerve-fiber layer (RNFL) thickness using a Cirrus HD-OCT (optic disc 200 × 200 cube) protocol. Sectoral structure-function relationships were studied in the glaucoma group.
Results
The velocity in the STV was lower in the glaucoma group (6.30 ± 1.6 mm/s) compared to the control group (8.6 ± 2.8 mm/s, p = 0.07), with no significant differences in the ITV. There were no significant differences in STV or ITV diameters between the groups. We found no relationship between either STV or ITV retinal blood flow and visual field or RNFL thickness.
Conclusion
Our prototype AO-LDV allowed accurate measurement of RBF in patients with glaucoma and showed that RBF was not reduced in the early or moderate stages of glaucoma. These preliminary results should be confirmed in a larger study, especially in late-stage glaucoma.
{"title":"Retinal blood flow in eyes with primary open-angle glaucoma using a new Adaptive Optics Laser Doppler Velocimeter device","authors":"Ohud Altuwaym , Martial Geiser , Thibaud Mautuit , Frédéric Truffer , Christophe Chiquet","doi":"10.1016/j.mvr.2025.104858","DOIUrl":"10.1016/j.mvr.2025.104858","url":null,"abstract":"<div><h3>Purpose</h3><div>To measure retinal blood flow (RBF) in the retinal veins of patients with primary open-angle glaucoma (POAG) and to compare it with healthy controls. A secondary objective was to determine any correlation between RBF and visual field (VF) loss or retinal nerve-fiber layer (RNFL) thickness.</div></div><div><h3>Method</h3><div>Twelve patients with POAG and 11 healthy controls were included in a prospective single-center study. Our prototype Adaptive Optics Laser Doppler Velocimeter (AO-LDV) consisted of a laser Doppler velocimeter combined with an adaptive optic fundus camera (rtx1, Imagine Eyes®) allowing measurement of blood vessel diameter and therefore, calculation of blood flow within the vessel. Blood flow in the superior temporal vein (STV) was compared with that in the inferior temporal vein (ITV). All subjects underwent eye examinations including visual field (Humphrey 24-2 SITA-standard strategy) and measurement of retinal nerve-fiber layer (RNFL) thickness using a Cirrus HD-OCT (optic disc 200 × 200 cube) protocol. Sectoral structure-function relationships were studied in the glaucoma group.</div></div><div><h3>Results</h3><div>The velocity in the STV was lower in the glaucoma group (6.30 ± 1.6 mm/s) compared to the control group (8.6 ± 2.8 mm/s, <em>p</em> = 0.07), with no significant differences in the ITV. There were no significant differences in STV or ITV diameters between the groups. We found no relationship between either STV or ITV retinal blood flow and visual field or RNFL thickness.</div></div><div><h3>Conclusion</h3><div>Our prototype AO-LDV allowed accurate measurement of RBF in patients with glaucoma and showed that RBF was not reduced in the early or moderate stages of glaucoma. These preliminary results should be confirmed in a larger study, especially in late-stage glaucoma.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104858"},"PeriodicalIF":2.7,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-08DOI: 10.1016/j.mvr.2025.104857
Chunli Yang , Huijuan Zhao , Xiaomin Wu , Wei Tuo , Ling Hou , Dahai Chai , Guanghua Li
This study examined the autophagy and apoptosis of vascular endothelial cells in spontaneously hypertensive rats (SHRs) under intermittent heat stress and determined whether the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51 like autophagy activating kinase (ULK1) pathway is involved in autophagy regulation. Wistar-Kyoto (WKY) rats were assigned to control (WKY-CN), intermittent heat stress (WKY-8), and continuous heat stress (WKY-24) groups. SHRs were also assigned to three groups: SHR-CN, SHR-8, and SHR-24. Western blotting assay, immunohistochemical assay, and immunofluorescence assay were performed for observing expression of proteins related to autophagy and apoptosis and the AMPK/mTOR/ULK1 pathway. Vascular endothelial cells underwent autophagy and apoptosis following heat stress, as revealed by high expression of autophagy- and apoptosis-related proteins. Heat stress elevated AMPK and ULK1 expression levels, whereas it decreased mTOR phosphorylation in SHR-8 and SHR-24 groups. Finally, the rats in SHR-8 group were administered an autophagy inducer (rapamycin, Rapa) and inhibitor (3-Methyladenine, 3-MA), respectively, for evaluating autophagy induction and inhibition. Following Rapa administration, LC3-II/LC3-I and Caspase-3 expression levels were elevated in the intermittent heat stress groups as compared to those in the control groups; in contrast, 3-MA attenuated cell death in the intermittent heat stress groups. Overall, this study demonstrated that intermittent heat stress elicits autophagy and apoptosis processes in vascular endothelial cells and that the AMPK/mTOR/ULK1 pathway participates in regulating autophagy and apoptosis.
{"title":"Intermittent heat stress facilitates the autophagy and apoptosis of the vascular endothelium in spontaneously hypertensive rats via the AMPK/mTOR/ULK1 pathway","authors":"Chunli Yang , Huijuan Zhao , Xiaomin Wu , Wei Tuo , Ling Hou , Dahai Chai , Guanghua Li","doi":"10.1016/j.mvr.2025.104857","DOIUrl":"10.1016/j.mvr.2025.104857","url":null,"abstract":"<div><div>This study examined the autophagy and apoptosis of vascular endothelial cells in spontaneously hypertensive rats (SHRs) under intermittent heat stress and determined whether the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51 like autophagy activating kinase (ULK1) pathway is involved in autophagy regulation. Wistar-Kyoto (WKY) rats were assigned to control (WKY-CN), intermittent heat stress (WKY-8), and continuous heat stress (WKY-24) groups. SHRs were also assigned to three groups: SHR-CN, SHR-8, and SHR-24. Western blotting assay, immunohistochemical assay, and immunofluorescence assay were performed for observing expression of proteins related to autophagy and apoptosis and the AMPK/mTOR/ULK1 pathway. Vascular endothelial cells underwent autophagy and apoptosis following heat stress, as revealed by high expression of autophagy- and apoptosis-related proteins. Heat stress elevated AMPK and ULK1 expression levels, whereas it decreased mTOR phosphorylation in SHR-8 and SHR-24 groups. Finally, the rats in SHR-8 group were administered an autophagy inducer (rapamycin, Rapa) and inhibitor (3-Methyladenine, 3-MA), respectively, for evaluating autophagy induction and inhibition. Following Rapa administration, LC3-II/LC3-I and Caspase-3 expression levels were elevated in the intermittent heat stress groups as compared to those in the control groups; in contrast, 3-MA attenuated cell death in the intermittent heat stress groups. Overall, this study demonstrated that intermittent heat stress elicits autophagy and apoptosis processes in vascular endothelial cells and that the AMPK/mTOR/ULK1 pathway participates in regulating autophagy and apoptosis.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104857"},"PeriodicalIF":2.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.mvr.2025.104842
Chihiro Matsui , Reiko Tsukuura , Toko Miyazaki , Shigeki Ishibashi , Takakuni Tanaka , Takayoshi Nishimura , Go Arai , Joseph M. Escandón , Hatan Mortada , Takumi Yamamoto
Introduction
Lymphedema is a chronic, progressive disorder characterized by impaired lymphatic transport, tissue swelling, and fibrosis. This study used video-capillaroscopy, a high-resolution imaging technique, to assess superficial collecting lymphatic vessels and their vasa vasorum in patients with lymphedema. By comparing these microvascular structures to those in healthy tissue, we aimed to identify early vascular changes contributing to disease progression.
Methods
VC recordings were retrospectively analyzed from 28 limbs in 17 patients with lower extremity lymphedema and 53 lymphatic vessels in 12 cancer patients undergoing reconstructive surgery. In the latter group, observations were performed on normal subcutaneous tissue exposed at the donor site during flap harvest. These areas showed no tumor involvement, regional metastasis, or prior chemotherapy/radiotherapy. Thus, all normal tissue observations were made on untreated, unaffected sites. VCLs were classified into six stages (0–5) based on morphology and flow. Vessel diameter and red blood cell (RBC) velocity were measured. Statistical significance was set at p < 0.05.
Results
In normal donor tissue, mean VCL main vessel diameter and RBC velocity were 0.038 ± 0.031 mm and 185 ± 160.5 μm/s. In lymphedema, these values were reduced to 0.033 ± 0.024 mm and 28.3 ± 36.8 μm/s (p < 0.001). VCL Stage 0 showed preserved flow (p = 0.178), while Stages 1–5 exhibited progressive impairment.
Conclusion
These findings suggest that early ischemic changes in the vasa vasorum may precede lymphatic dysfunction and fibrosis in lymphedema. Preserving microvascular integrity should be a therapeutic focus, alongside drainage support. Further studies are needed to clarify clinical relevance and optimize treatment strategies.
{"title":"Comparative analysis of superficial collecting lymph vessels in normal tissue and lymphedema using video-capillaroscopy","authors":"Chihiro Matsui , Reiko Tsukuura , Toko Miyazaki , Shigeki Ishibashi , Takakuni Tanaka , Takayoshi Nishimura , Go Arai , Joseph M. Escandón , Hatan Mortada , Takumi Yamamoto","doi":"10.1016/j.mvr.2025.104842","DOIUrl":"10.1016/j.mvr.2025.104842","url":null,"abstract":"<div><h3>Introduction</h3><div>Lymphedema is a chronic, progressive disorder characterized by impaired lymphatic transport, tissue swelling, and fibrosis. This study used video-capillaroscopy, a high-resolution imaging technique, to assess superficial collecting lymphatic vessels and their vasa vasorum in patients with lymphedema. By comparing these microvascular structures to those in healthy tissue, we aimed to identify early vascular changes contributing to disease progression.</div></div><div><h3>Methods</h3><div>VC recordings were retrospectively analyzed from 28 limbs in 17 patients with lower extremity lymphedema and 53 lymphatic vessels in 12 cancer patients undergoing reconstructive surgery. In the latter group, observations were performed on normal subcutaneous tissue exposed at the donor site during flap harvest. These areas showed no tumor involvement, regional metastasis, or prior chemotherapy/radiotherapy. Thus, all normal tissue observations were made on untreated, unaffected sites. VCLs were classified into six stages (0–5) based on morphology and flow. Vessel diameter and red blood cell (RBC) velocity were measured. Statistical significance was set at <em>p</em> < 0.05.</div></div><div><h3>Results</h3><div>In normal donor tissue, mean VCL main vessel diameter and RBC velocity were 0.038 ± 0.031 mm and 185 ± 160.5 μm/s. In lymphedema, these values were reduced to 0.033 ± 0.024 mm and 28.3 ± 36.8 μm/s (<em>p</em> < 0.001). VCL Stage 0 showed preserved flow (<em>p</em> = 0.178), while Stages 1–5 exhibited progressive impairment.</div></div><div><h3>Conclusion</h3><div>These findings suggest that early ischemic changes in the vasa vasorum may precede lymphatic dysfunction and fibrosis in lymphedema. Preserving microvascular integrity should be a therapeutic focus, alongside drainage support. Further studies are needed to clarify clinical relevance and optimize treatment strategies.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104842"},"PeriodicalIF":2.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.mvr.2025.104846
Aurelia Bucciarelli, Dominik Obrist
Efficient oxygen delivery in the brain relies on a finely tuned balance between vascular architecture and dynamic flow regulation. While red blood cells (RBCs) passively flow through the capillary network, neurovascular coupling ensures that the blood supply adapts to meet the metabolic demands of active neurons. Pericytes, contractile cells embedded in the capillary walls, play a key role in this process by modulating capillary diameter in response to neural signals. While pericytes are believed to enable rapid and localized blood flow regulation, their contributions in time and space remain debated. This study investigates the effects of pericyte-like vessel dilation (i.e., pericyte relaxation) on RBC distribution and flow dynamics using an in vitro microfluidic model. We investigate how pericyte-induced dynamic cross-sectional changes affect RBC distribution and velocity in a capillary network. By employing a programmable pressure pump to simulate gradual variations in capillary diameter, we observed that short-time dilation increased RBC velocity and hematocrit near the dilation site, enhancing localized perfusion. In contrast, prolonged dilation led to a network-wide RBC redistribution minimizing hydraulic resistance, ultimately depleting hematocrit due to the network Fåhræus effect. These findings highlight the dynamic and adaptive nature of capillary blood flow, where sustained localized changes can propagate into systemic effects over time. More broadly, this study provides new insights into the interplay between localized flow regulation and systemic capillary network dynamics, revealing how geometric and dynamic factors govern RBC behavior and perfusion.
{"title":"Influence of pericyte-like vessel dilation on RBC flux in an In Vitro microvascular network","authors":"Aurelia Bucciarelli, Dominik Obrist","doi":"10.1016/j.mvr.2025.104846","DOIUrl":"10.1016/j.mvr.2025.104846","url":null,"abstract":"<div><div>Efficient oxygen delivery in the brain relies on a finely tuned balance between vascular architecture and dynamic flow regulation. While red blood cells (RBCs) passively flow through the capillary network, neurovascular coupling ensures that the blood supply adapts to meet the metabolic demands of active neurons. Pericytes, contractile cells embedded in the capillary walls, play a key role in this process by modulating capillary diameter in response to neural signals. While pericytes are believed to enable rapid and localized blood flow regulation, their contributions in time and space remain debated. This study investigates the effects of pericyte-like vessel dilation (i.e., pericyte relaxation) on RBC distribution and flow dynamics using an <em>in vitro</em> microfluidic model. We investigate how pericyte-induced dynamic cross-sectional changes affect RBC distribution and velocity in a capillary network. By employing a programmable pressure pump to simulate gradual variations in capillary diameter, we observed that short-time dilation increased RBC velocity and hematocrit near the dilation site, enhancing localized perfusion. In contrast, prolonged dilation led to a network-wide RBC redistribution minimizing hydraulic resistance, ultimately depleting hematocrit due to the network Fåhræus effect. These findings highlight the dynamic and adaptive nature of capillary blood flow, where sustained localized changes can propagate into systemic effects over time. More broadly, this study provides new insights into the interplay between localized flow regulation and systemic capillary network dynamics, revealing how geometric and dynamic factors govern RBC behavior and perfusion.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104846"},"PeriodicalIF":2.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-30DOI: 10.1016/j.mvr.2025.104855
Nien-Wen Hu , M.M.N. Hossain , Julia Withrow , Ryan Walker , Ali Kazempour , Nikolaos Tsoukias , Donald G. Welsh , Walter L. Murfee , Peter Balogh
The objective of this study was to computationally estimate the effects of vessel specific vasoconstriction on immediate shear stress changes across microvascular networks. Shear stress due to microvascular blood flow is an established initiator of ion-mediated signaling along microvessels which regulates control of microcirculatory blood flow. Yet, beyond initiating local vasomotion in a vessel, shear stress as a vasoconduction signal itself and characteristics of hydrodynamic propagation via blood flow are not well understood. In the current work, we use images of mesenteric microvascular networks from adult rat tissues and a network segmental blood flow model to simulate various vessel constriction scenarios and estimate subsequent shear stress changes and distances these changes spread from the site of constriction. Scenarios involving both arteriolar constriction and capillary constriction are considered, in addition to a microvascular network from muscle tissue. The findings generally reveal heterogenous and physiologically relevant shear stress changes across the networks for all cases, with magnitudes spanning a wide range and can exceed 30 dyne/cm2. Further, physiological relevant wall shear changes were predicted at distances several mm from the stimulus site. Spatial patterns of shear stress change relative to network topology and capillary density are also identified. Altogether, the results invigorate consideration and discussion about shear stress as a potential player in vasoconduction responses.
{"title":"Identification of shear stress as a potential vasoconduction signal across microvascular networks","authors":"Nien-Wen Hu , M.M.N. Hossain , Julia Withrow , Ryan Walker , Ali Kazempour , Nikolaos Tsoukias , Donald G. Welsh , Walter L. Murfee , Peter Balogh","doi":"10.1016/j.mvr.2025.104855","DOIUrl":"10.1016/j.mvr.2025.104855","url":null,"abstract":"<div><div>The objective of this study was to computationally estimate the effects of vessel specific vasoconstriction on immediate shear stress changes across microvascular networks. Shear stress due to microvascular blood flow is an established initiator of ion-mediated signaling along microvessels which regulates control of microcirculatory blood flow. Yet, beyond initiating local vasomotion in a vessel, shear stress as a vasoconduction signal itself and characteristics of hydrodynamic propagation via blood flow are not well understood. In the current work, we use images of mesenteric microvascular networks from adult rat tissues and a network segmental blood flow model to simulate various vessel constriction scenarios and estimate subsequent shear stress changes and distances these changes spread from the site of constriction. Scenarios involving both arteriolar constriction and capillary constriction are considered, in addition to a microvascular network from muscle tissue. The findings generally reveal heterogenous and physiologically relevant shear stress changes across the networks for all cases, with magnitudes spanning a wide range and can exceed 30 dyne/cm<sup>2</sup>. Further, physiological relevant wall shear changes were predicted at distances several mm from the stimulus site. Spatial patterns of shear stress change relative to network topology and capillary density are also identified. Altogether, the results invigorate consideration and discussion about shear stress as a potential player in vasoconduction responses.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104855"},"PeriodicalIF":2.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-24DOI: 10.1016/j.mvr.2025.104847
Hongjin An , Junju Zhu , Qianqian Li
Background
This study investigated the effects and possible mechanisms of Protein expression of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab on cardiac function in rats with acute myocardial infarction (AMI).
Methods
The AMI model was established by ligating the left anterior descending coronary artery in rats. The mRNA expression of PCSK9 in myocardial tissues was detected by real-time fluorescent quantitative PCR (RT-qPCR). Echocardiography was used to examine the cardiac function indexes. Hematoxylin-eosin (HE) and Masson stainings were used to detect myocardial pathologic injury. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to detect myocardial infarction area. Serum levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), cardiac troponin T (cTnT), interleukin-1β (IL-1β), interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) were detected by ELISA. CD31 and vascular endothelial growth factor (VEGF) positive expression was detected by immunohistochemistry. Protein expression levels of PCSK9, Bax, Bcl-2, cleaved-caspase3, receptor interacting protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like (MLKL), and p-MLKL were detected in myocardial tissues by western blot.
Results
The mRNA level and protein expression of PCSK9 were significantly increased in AMI rats. PCSK9 inhibitor evolocumab reduced the levels of LDL-C and TC in serum, thereby improving dyslipidemia. And, evolocumab up-regulated the levels of left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and down-regulated the levels of left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic volume (LVESV), and left ventricular end diastolic volume (LVEDV), which in turn improved cardiac function. In addition, evolocumab attenuated myocardial pathological injury, reduced myocardial infarction area, lowered the levels of LDH, CK-MB, cTnT, IL-1β, IL-17, and TNF-α, and inhibited apoptosis rate, down-regulated Bax, cleaved-caspase3, RIPK1, RIPK3, MLKL, p-MLKL expression, and up-regulated Bcl-2 protein expression, CD31 and VEGF positive expression.
Conclusion
The PCSK 9 inhibitor evolocumab improved cardiac function in AMI rats, and the mechanism may be related to the RIPK1/RIPK3/MLKL pathway.
{"title":"PCSK9 inhibitor improved cardiac function after acute myocardial infarction in rats","authors":"Hongjin An , Junju Zhu , Qianqian Li","doi":"10.1016/j.mvr.2025.104847","DOIUrl":"10.1016/j.mvr.2025.104847","url":null,"abstract":"<div><h3>Background</h3><div>This study investigated the effects and possible mechanisms of Protein expression of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab on cardiac function in rats with acute myocardial infarction (AMI).</div></div><div><h3>Methods</h3><div>The AMI model was established by ligating the left anterior descending coronary artery in rats. The mRNA expression of PCSK9 in myocardial tissues was detected by real-time fluorescent quantitative PCR (RT-qPCR). Echocardiography was used to examine the cardiac function indexes. Hematoxylin-eosin (HE) and Masson stainings were used to detect myocardial pathologic injury. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to detect myocardial infarction area. Serum levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), cardiac troponin T (cTnT), interleukin-1β (IL-1β), interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) were detected by ELISA. CD31 and vascular endothelial growth factor (VEGF) positive expression was detected by immunohistochemistry. Protein expression levels of PCSK9, Bax, Bcl-2, cleaved-caspase3, receptor interacting protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like (MLKL), and p-MLKL were detected in myocardial tissues by western blot.</div></div><div><h3>Results</h3><div>The mRNA level and protein expression of PCSK9 were significantly increased in AMI rats. PCSK9 inhibitor evolocumab reduced the levels of LDL-C and TC in serum, thereby improving dyslipidemia. And, evolocumab up-regulated the levels of left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and down-regulated the levels of left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic volume (LVESV), and left ventricular end diastolic volume (LVEDV), which in turn improved cardiac function. In addition, evolocumab attenuated myocardial pathological injury, reduced myocardial infarction area, lowered the levels of LDH, CK-MB, cTnT, IL-1β, IL-17, and TNF-α, and inhibited apoptosis rate, down-regulated Bax, cleaved-caspase3, RIPK1, RIPK3, MLKL, p-MLKL expression, and up-regulated Bcl-2 protein expression, CD31 and VEGF positive expression.</div></div><div><h3>Conclusion</h3><div>The PCSK 9 inhibitor evolocumab improved cardiac function in AMI rats, and the mechanism may be related to the RIPK1/RIPK3/MLKL pathway.</div></div>","PeriodicalId":18534,"journal":{"name":"Microvascular research","volume":"162 ","pages":"Article 104847"},"PeriodicalIF":2.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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